The toxicity of tau in Alzheimer disease: turnover, targets and potential therapeutics

•  Introduction •  Pathological modifications of tau ‐  Tau phosphorylation ‐  Tau truncation ‐  NFTs are not the primary toxic species•  Tau turnover and possible deficits in Alzheimer disease •  Tau toxicity in Alzheimer disease •  Potential ‘tau‐centric’ therapeutic strategies ‐  Tau aggregation inhibitors ‐  Microtubule stabilizing agents ‐  Tau immunotherapy ‐  Autophagy activators ‐  Mitochondria targeted therapies•  Summary and conclusionsIt has been almost 25 years since the initial discovery that tau was the primary component of the neurofibrillary tangles (NFTs) in Alzheimer disease (AD) brain. Although AD is defined by both β‐amyloid (Aβ) pathology (Aβ plaques) and tau pathology (NFTs), whether or not tau played a critical role in disease pathogenesis was a subject of discussion for many years. However, given the increasing evidence that pathological forms of tau can compromise neuronal function and that tau is likely an important mediator of Aβ toxicity, there is a growing awareness that tau is a central player in AD pathogenesis. In this review we begin with a brief history of tau, then provide an overview of pathological forms of tau, followed by a discussion of the differential degradation of tau by either the proteasome or autophagy and possible mechanisms by which pathological forms of tau may exert their toxicity. We conclude by discussing possible avenues for therapeutic intervention based on these emerging themes of tau’s role in AD.